?-Synucleinopathies are a subset of neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB) and multiple system atrophy (MSA) (1), which are characterized by abnormal accumulation of misfolded ?-synuclein (?-syn) protein in neurons or glial cells. Emerging evidence suggests that the cell-to-cell transmission of pathological ?-syn substantially cause neurodegeneration. However, the molecular mechanism of ?-syn transmission is poorly understood. We have identified three transmembrane proteins that strongly bind with ?-syn PFF: (i) lymphocyte activation gene-3 (LAG3), (ii) amyloid ? precursor-like protein 1 (APLP1), and (iii) neurexin 1-?. LAG3 is an essential receptor, mediating internalization of ?-syn PFF; however, substantial ?-syn PFF binds to LAG3-/- (knockout) neurons, suggesting that a unidentified candidate(s) (e.g. APLP1) binds with pathologic ?-syn, and facilitate the internalization. In this proposal, we hypothesize: (i) APLP1 is an essential receptor, that mediates ?-syn transmission; (ii) APLP1-LAG3 complex synergistically mediates ?-syn transmission; (iii) depletion of APLP1, LAG3, or APLP1- LAG3 complex, can reduce ?-syn-induced neurodegeneration of ?-syn transgenic mice. Accordingly, experiments are proposed to characterize the roles of APLP1, LAG3 and the AL complex in mediating the pathogenesis of ?-synucleinopathies, in cell-to-cell transmission models and the ?-syn transgenic mouse model. Experiments in two mice models with ?-synucleinopathies, will be complemented by studies in cells and cell-free experiments, thus allowing the deciphering of each spreading step in the interaction of APLP1, LAG3, or the AL complex with pathologic ?-syn. The successful completion of these studies will greatly enhance our understanding of the molecular mechanisms of ?-syn cell-to-cell transmission via receptors, by: (i) identifying APLP1 as a novel receptor that mediates ?-syn spreading, (ii) understanding the synergistic effect of the AL complex on mediating binding and internalization of ?-syn PFF, (iii) providing essential preliminary evaluation of anti-LAG3 antibody as a potential therapeutic agent against PD and related ?-synucleinopathies, and (iv) understanding the roles of APLP1, LAG3, and the AL complex in mediating neurodegeneration of ?-syn transgenic mice.